A Concerted HIF-1αMT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells 英文参考文献.docVIP

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A Concerted HIF-1αMT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells 英文参考文献.doc

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A Concerted HIF-1αMT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells 英文参考文献

AConcertedHIF-1a/MT1-MMPSignallingAxisRegulates theExpressionofthe3BP2AdaptorProteininHypoxic MesenchymalStromalCells Se′bastienProulx-Bonneau.,AmelGuezguez.,BorhaneAnnabi* Laboratoired’OncologieMole′culaire, CentrederechercheBIOMED,De′partementdeChimie,Universite′ duQue′bec a` Montre′al,Quebec,Canada Abstract Increasedplasticity,migratoryandimmunosuppressiveabilitiescharacterizemesenchymalstromalcells(MSC)whichenable them to be active participants in the development of hypoxic solid tumours. Our understanding of the oncogenic adaptationofMSCtohypoxiahoweverlackstheidentificationandcharacterizationofspecificbiomarkers.Inthisstudy,we assessedthehypoxicregulationof3BP2/SH3BP2(AblSH3-bindingprotein2),animmuneresponseadaptor/scaffoldprotein which regulates leukocyte differentiation and motility. Gene silencing of 3BP2 abrogated MSC migration in response to hypoxic cues and generation of MSC stably expressing the transcription factor hypoxia inducible factor 1alpha (HIF-1a) resulted in increased endogenous 3BP2 expression as well as cell migration. Analysis of the 3BP2 promoter sequence revealed only one potential HIF-1a binding site within the human but none in the murine sequence. An alternate early signallingcascadethatregulated3BP2expressionwasfoundtoinvolvemembranetype-1matrixmetalloproteinase(MT1- MMP)transcriptionalregulationwhichgenesilencingabrogated3BP2expressioninresponsetohypoxia.Collectively,we provideevidenceforaconcertedHIF-1a/MT1-MMPsignallingaxisthatexplainstheinductionofadaptorprotein3BP2and whichmaylinkproteinbindingpartnerstogetherandstimulateoncogenicMSCmigration.Thesemechanisticobservations supportthepotentialformalignanttransformationofMSCwithinhypoxictumourstromaandmaycontributetoevasionof theimmunesystembyatumour. Citation:Proulx-BonneauS,GuezguezA,AnnabiB(2011)AConcertedHIF-1a/MT1-MMPSignallingAxisRegulatestheExpressionofthe3BP2AdaptorProteinin HypoxicMesenchymalStromalCells.PLoSONE6(6):e21511.doi:10.1371/journal.pone.0021511 Editor:Cesar